# US 10,370,361 B2 · Polymorphs and solid forms of a pyrimidinylamino-pyrazole compound, and methods of production

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,370,361 B2
- Document ID: US10370361B2
- Status: Granted
- Kind: B2
- Application number: 16/197,037
- Filed: 2018-11-20
- Published: 2019-06-27
- Granted: 2019-08-06
- Earliest claimed: 2017-11-21
- Assignees: Denali Therapeutics Inc.
- Applicants: Denali Therapeutics Inc.
- Inventors: Travis Remarchuk; Anantha Sudhakar
- Web page: https://patentgrep.com/patent/US10370361B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61K 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure relates to crystalline polymorph and amorphous forms of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile or solvates, tautomers, and pharmaceutically acceptable salts or cocrystals thereof, and processes for their preparation.

## Claims

### Claim 1

A crystalline compound, 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile, selected from:
a Form B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.0, 7.3, 16.1, 16.3, 24.1, 25.1, and 26.6;
a Form C polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.4, 15.1, 21.2, 25.7, and 27.8; and
a Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 9.2, 14.0, 14.8, 19.7, and 20.0.

### Claim 2 (depends on 1)

The crystalline compound of claim 1, selected from:
a Form C polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.4, 8.1, 8.6, 8.8, 9.9, 10.2, 12.9, 13.8, 15.1, 15.4, 16.5, 19.8, 21.2, 22.1, 23.7, 25.7, and 27.8; and
a Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.0, 8.7, 9.2, 9.8, 10.4, 12.9, 13.4, 14.0, 14.8, 16.4, 18.5, 19.7, 20.0, 20.8, 23.1, 23.3, 23.9, 25.5, and 25.7.

### Claim 3 (depends on 1)

The crystalline compound of claim 1, wherein the compound is in substantially pure form.

### Claim 4 (depends on 1)

The crystalline compound of claim 1, wherein the X-ray powder diffraction pattern is made using CuKα1 radiation.

### Claim 5 (depends on 1)

The crystalline compound of claim 1, wherein the compound is the Form B polymorph having an X-ray powder diffraction pattern substantially free of peaks at approximately 12.9 and 14.8±0.05 degrees 2-theta.

### Claim 6 (depends on 1)

The crystalline compound of claim 1, wherein the Form B polymorph is a cyclohexanol solvate.

### Claim 7 (depends on 1)

The Form B polymorph of claim 1 wherein a differential scanning calorimetry DSC shows two melting endotherms at about 87.9 and 103.2° C. onset.

### Claim 8 (depends on 1)

The crystalline compound of claim 1, wherein the compound is the Form C polymorph having an X-ray powder diffraction pattern substantially free of peaks at 13.6 and 14.8±0.05 degrees 2-theta.

### Claim 9 (depends on 1)

The crystalline compound of claim 1, wherein the compound is the Form C polymorph further comprising peaks at 16.5 and 22.1±0.05 degrees 2-theta.

### Claim 10 (depends on 1)

The crystalline compound of claim 1, wherein the Form C polymorph is an anhydrate.

### Claim 11 (depends on 1)

The Form C polymorph of claim 1 characterized by the X-ray powder diffraction pattern shown in FIG. 10.

### Claim 12 (depends on 1)

The Form C polymorph of claim 1 wherein a differential scanning calorimetry DSC shows a melting endotherm at about 127.8° C. onset.

### Claim 13 (depends on 1)

The crystalline compound of claim 1, wherein the compound is the Form D polymorph having an X-ray powder diffraction pattern substantially free of peaks at 13.6±0.05 degrees 2-theta.

### Claim 14 (depends on 1)

The crystalline compound of claim 1, wherein the Form D polymorph is an anhydrate.

### Claim 15 (depends on 1)

The Form D polymorph of claim 1 characterized by the X-ray powder diffraction pattern shown in FIG. 12.

### Claim 16 (depends on 1)

The Form D polymorph of claim 1 wherein a differential scanning calorimetry DSC shows a melting endotherm at about 129.1° C. onset.

### Claim 17 (depends on 1)

The crystalline compound of claim 1, exhibiting a mass increase of less than about 1% when subjected to an increase in relative humidity from about 0% to about 95% relative humidity for about 180 minutes.

### Claim 18 (depends on 1)

The crystalline compound of claim 1, which is stable upon exposure to about 40° C. and about 75% relative humidity for at least 6 months.

### Claim 19

A crystalline compound, 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile exhibiting an X-ray powder diffraction pattern having characteristic peaks expressed in ±0.3 degrees 2-theta at approximately 6.4, 15.1, 21.2, 25.7, and 27.8.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the crystalline polymorph of claim 1, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20 in the form of a tablet.

### Claim 22 (depends on 20)

The pharmaceutical composition of claim 20 wherein the therapeutically effective amount is from 1 to 200 mg.

### Claim 23 (depends on 20)

The pharmaceutical composition of claim 20 wherein the crystalline polymorph is milled.

### Claim 24

A process for preparing a crystalline polymorph comprising heating at 50° C. or above 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile in methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, isopropyl acetate, or combinations thereof and a non-polar solvent such as heptane, and then cooling the mixture whereby a Form C crystalline polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.4, 15.1, 21.2, 25.7, and 27.8 degrees 2-theta is formed.

### Claim 25 (depends on 24)

The process of claim 24 wherein the mixture is seeded.

### Claim 26

A process for preparing a crystalline polymorph comprising heating at 50° C. or above, an anhydrous solution of 2-methyl-2-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)propanenitrile in methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, isopropyl acetate, or combinations thereof, and a non-polar solvent such as heptane, and then cooling the mixture whereby a Form D crystalline polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 9.2, 14.0, 14.8, 19.7, and 20.0 degrees 2-theta is formed.

### Claim 27 (depends on 26)

The process of claim 26 wherein the mixture is seeded.